Method and apparatus for delivery of medication

ABSTRACT

An implanted device such as a stent is provided which is capable of holding an induced charge or sufficient magnitude that the device may, by electrostatic means, attract the bioactive material to itself. The charge, either positive or negative, or relative to the bioactive material sufficiently positive or negative, is deposited into the implantable device via an exterior induction coil. The implantable device itself becomes an introduced “dosage form”, becoming part of a biologically closed electric circuit, through which the bioactive material is attracted to the implanted device.

FIELD OF THE INVENTION

The present invention is directed to a method and apparatus fordelivering medication over a prolonged period. The method includedcharging or recharging an implanted device which has been or can beimpregnated with a bioactive ingredient without the requirement forremoving the device from the body.

BACKGROUND OF THE INVENTION

It has become common to treat a variety of medical conditions bytemporarily or permanently introducing an implantable medical devicepartly or completely into the esophagus, trachea, colon, biliary tract,urinary tract, vascular system, or other locations within a human orveterinary patients. Many treatments of the vascular or other systemsentail introducing a device such as a stent, a catheter, a balloon, awire guide, a cannula, or the like.

Some drawbacks can be encountered during use of a stent or otherimplantable medical device. For example, when a device is introducedinto and manipulated through the vascular system of a patient, the bloodvessel walls can be disturbed or injured. Clot formation or thrombosisoften results at the injured site, causing stenosis (closure) of theblood vessel. Moreover, if the medical device is left within the patientfor an extended period of time, thrombus often forms on the deviceitself, again causing stenosis. As a result, the patient is placed atrisk of a variety of complications, including heart attack, pulmonaryembolism, and stroke. Thus, the use of such a medical device can entailthe risk of precisely the problems that its use was intended toameliorate.

The efficacy of a stent can be assessed by evaluating a number offactors, such as thrombosis, neotimimal hyperplasia, smooth muscle cellmigration and proliferation following implantation of the stent, injuryto the artery wall, overall loss of luminal patency, stent diameter invivo, thickness of the stent, and leukocyte adhesion to the luminallining of tented arteries. However, the chief areas of concern are earlysubacute thrombosis and eventual restenosis of the blood vessel due tointimal hyperplasia.

Other conditions and diseases are treatable with stents, catheters,cannulae, and other medical devices inserted into the esophagus,trachea, colon, biliary tract, urinary tract, and other locations in thebody. A wide variety of bioactive materials, including drugs,therapeutic agents, diagnostic agents, and other materials havingbiological or pharmacological activity within a patient, have beenapplied to such medical devices for the purpose of introducing suchmaterials into the patient. Unfortunately, the durable application ofbioactive materials to these medical devices and the like, sufficientfor such introduction to occur, is often problematic. A range ofimpregnated or layered materials have been applied to such devices topermit the timed release of bioactive materials from such devices, oreven to permit bioactive materials to be applied to such devices at all.Therapeutic pharmacological agents have been developed to improvesuccessful placement of the medical device as well as to be delivered tothe site of device implantation. Among the drugs that can be deliveredvia impregnated or loaded medical devices are those that can treatrestenosis, tissue inflammation, promote endotheliazation or any otherdisease that may inhibit the successful implantation and retention ofthe device.

Implantable devices made of biologically acceptable metals werepreviously unable to deliver localized bioactive materials to tissues atthe location treated by the device. However, there are polymericmaterials that can be loaded with and release bioactive materials,including drugs or other pharmacological treatment, which can be usedfor drug delivery.

Yan, in U.S. Pat. No. 5,843,172, the entire contents of which are herebyincorporated by reference, describes a stent made of metal which hasporous cavities in the metallic portion of the stent so that the drugscan be loaded directly into the pores without substantially weakeningthe structural and mechanical characteristics of the prosthesis.However, once the bioactive material has been depleted from the stent,if it is still necessary to deliver the material to the site of thestent, the stent must be replaced.

SUMMARY OF THE INVENTION

It is an object of the present invention to overcome the aforesaiddeficiencies in the prior art.

It is another object of the present invention to provide an implantabledevice which can be recharged with a bioactive material.

It is a further object of the present invention to provide animplantable device which can be charged with a bioactive material.

According to the present invention, an implantable device such as astent is provided which is capable of holding an induced charge ofsufficient magnitude that the device may, by electrostatic means,attract bioactive material to itself. The charge, either positive ornegative, or relative to the bioactive material sufficiently positive ornegative, is deposited into the implantable device via an exteriorinduction coil. The implantable device itself becomes an introduced“dosage form”, becoming part of a biologically closed electric circuit,as shown in Nordenstrom, B. E., Biologically Closed Electrical Systems;Stockholm, Nordic Medical Publications, 1983. This mechanism is similarto that described in Sceusa, U.S. Pat. No. 6,414,033, the entirecontents of which are hereby incorporated by reference.

The bioactive ingredient, which may be in ionic form as described inSceusa, supra, or in a neutral complex that will dissociate tonically inthe presence of the charge of the implantable device, will then attachitself to the implantable device.

The implantable device must possess the correct electronic transfersystem to permit an induced charge to form, to be carried, and to beretained long enough to act electrostatically and attract the medicationto itself. Many materials having these properties are known, includingplastics and ceramics which have metal atoms covalently bonded into thematrix, or an entirely ceramic material without metal ions, having thecorrect electronic transfer system. Alternatively, the implantabledevice can be made with a metallic or capacitive strip entirely embeddedwithin the device to drive the accretion of medication into the matrixof the device. In yet another embodiment, the implantable device can bemade of porous metal, such as disclosed in Yan, U.S. Pat. No. 5,843,172.Any conventional physiologically acceptable material which has theneeded electron transfer (capacitance) systems can be used in thepresent invention.

To recharge or charge the implantable device, the bioactive material canbe delivered intravenously or trans-membrane by one of two systems:

1. Intravenous injection, which is minimally invasive; or

2. Teorell-Meyer dosage or “reverse” Teorell-Meyer forms, depending uponthe anatomy and location of the implantable medical device.

The bioactive material should be in a “reverse” Teorell-Meyer dosageform as follows:

1. It may be a neutral complex of the bioactive ingredient and asuitable carrier molecule, or a synthetic carrier molecule, such thatthe K_(d) (the constant of dissociation), which is the reciprocal of theK_(a) (constant of association), is less than the electrostatic force ofattraction exerted by the implantable device for the bioactive material.Thus, the medication will leave the carrier molecule and become embeddedin the implantable device.

2. The bioactive ingredient may be a stable charged complex with adirect attraction for the charge in the implantable device.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 illustrates a method for charging or recharging an implantabledevice in vivo.

FIGS. 2a and 2 b illustrate the electrostatic attraction of a bioactiveingredient for a carrier complex (2 a) iron an ionic complex (2 b).

FIG. 3 illustrates an implantable device.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a method for charging or recharging animplanted device with a bioactive material. FIG. 1 illustrates thepresent invention using a stent as the implanted device. Bioactivematerial 1, in ionic or neutral-dissociated complex, is introduced, inthis case, intravenously. An induction coil or device 2 ensures that theimplanted device is appropriately electrostatically charged. Thedifference in charge between the implanted device and the bioactiveagent causes the bioactive agent to be attracted to the implanteddevice.

All cells acquire the molecules and ions they need from the surroundingmilieu, usually the extracellular fluid. There is an unceasing trafficof molecules and ions ion and out of the cell through the cell's plasmamembrane. The cell membrane is a lipid bilayer that functions as aselective barrier for entry and exit of substances, i.e., the membraneis semipermeable. The membrane is permeable to water molecules and a fewother small, uncharged molecules such as oxygen and carbon dioxide.These molecules freely diffuse in and out of the cell. However, it isnot permeable to ions, small hydrophilic molecules that are attracted towater and other polar solvents, such as glucose, and macromolecules suchas proteins. Good lipid solubility is an important factor in theassessment of absorption. Unionized or neutral species are morelipid-soluble, and hence are more readily absorbed.

Simple diffusion is the most basic type of transport in the cell.Diffusion moves atoms, ions and molecules from a region of higherconcentration to a region of lower concentration. This differencebetween regions is referred to as a concentration gradient. If differingconcentrations of molecules, in two regions, are separated by apermeable membrane, the molecules will diffuse through the membrane froma higher to a lower concentration, until they reach an equalconcentration on both sides. Without permeability, diffusion will notoccur even if a difference in concentration exists. Osmosis is thediffusion of water through the membrane to equalize the concentrationson either side of the membrane. In osmosis, water must move because thedissolved particles are too large to pass through the membrane. The rateof diffusion of a particle across a membrane will vary depending on thesize, polarity, charge, and concentration of the molecule on the insideof the membrane versus the concentration on the outside of the membrane.

The Teorell-Meyer™ dosage forms depend upon bioelectricity for theirfunction. Two researchers were active in this field prior to thediscovery of these dosage forms: the Biologically Closed ElectricCircuit (BCEC) of Dr. Bjorn Nordenstrom, and the pioneering work onelectro-osmotic phenomena in general biology and membranes of Dr.Torsten Teorell and Dr. Karl Meyer. U.S. Pat. No. 6,414,033, is directedto dosage forms based upon the Teorell-Meyer gradient equations.

A biologically closed electric circuit is physiologically analogous toan ordinary electric circuit, except that predominantly ions, as well aselectrons, move along and through it. In biological material, theco-transport of electrons occurs in short redox steps. Ions aretransported electro-osmotically. Concentration, and consequently,electrical gradients, are maintained by Donnan Equilibria, which arelarge sheets of charge in the tissue proteins, and by ion pumpsfunctioning at the expense of ATP. The second half of the circuit, thereturn halve, takes place via passive or facilitated diffusion. Ionswill follow, or will respond to the flow of current according to theirnet charge, from one area of chare density to another area of differentcharge density, as part of the usual BCEC circulation. The localviscosity and the electrical path length, which is a vector quantity,play an important role. Vectors have the properties of force, distance(length), according to the gradients that comprise these vectors.Controlling the electrical vector makes it possible to control the pathof the ion, because the electrical vector is very many times strongerthan any of the other forces which act on an ion.

It is important to remember that a BCEC may be electrically closed butthermodynamically and physiologically open, so that a dosage form may beplaced therein. The present invention takes advantage of this propertyto induce a gradient artificially, using appropriate buffering,companion, and carrier molecules. Certain molecules may act as all threeat the same time, and the amino acids and their congeners have beenfound to be ideal for this purpose. By introducing the dosage form whichhas been specifically designed and buffered for a particularcompartment, the pH of the recipient compartment, in which the form isplaced, is changed relative to the target compartment, thus setting upan induced gradient and a corresponding concentration cell. This isprovided for by the Lewis acid-base definitions, which makes it possibleto consider all positive charges as a acids and all negative charges asbases.

Inducing the pH changes and thus taking control of the bio-electricalfield and corresponding electrical vector makes it possible tomanipulate the direction of ionic flow and transport. Since theelectrical vector is many times more powerful than the other vectorsacting in the system, it is possible to stop or reverse the ionic flowfor the time that the induced field is present. If the electrical vectoris coupled to act in the same direction as other vectors in the system,the effect is most powerful. The three vectors which are known to act inphysiological systems are the hydrostatic vector, the particulate(colligative) vector, and the electro-motive force (electro-osmotic)vector.

It should also be taken into account that the association constant(K_(a)) and its reciprocal, the dissociation constant (K_(c)), for anycomplex is pH dependent. In the context of an electrical gradient insidea concentration cell, it may also be considered electrically dependent.In other words, at one pH a complex may be completely associated, and atanother pH, may be almost completely dissociated.

For any given complex, a concentration cell has a continually changingspectrum of pH and association constants inherent within it. This changeover distance, which operates primarily, or most strongly, at theendpoints, is what allows the system to receive and deliver bioactivematerials in the way it does. By carefully choosing complexes and mixedligand complexes, with different K_(a), it is possible to deliver abioactive material directly to the location of the implanted device sothat the device is charged or recharged with the bioactive material.

It is commonly observed that charged particles do not easily penetratemembranes, because, generally, charged particles are not lipid soluble.This is generally true, but is not universally true. If a particle isfairly small, the charge comparatively large, and the membranerelatively thin, an ion can be dragged through the lipid bi-layermembrane. By arranging the electrical vector in the same direction asthe other diffusion vectors, this process can be improved by a factor ofthree, as shown in FIG. 2. This is particularly useful for certain ionsdelivered perpendicular to the membrane, such as the thin membranes ofthe nasal conchae in the nose.

If a charged complex is to be slid across a membrane, in a paralleldirection, until the complex reaches neutrality, the anatomy can be usedfor delivery. By controlling the pH difference between the recipient andtarget compartments, one can determine the length of the electricalvector with good accuracy. There the complex becomes neutral, and itpenetrates the membrane in the usual way.

As a non-limiting example, the largest and best known of the BCECs isthat which exists between the mouth and the nose. This area isconvenient and easy to test, and lends itself to experimentation. Themouth-nose circuit has a natural partition in the hard and soft palates,which can be easily modeled as an electrophoretic sheet. The fluids ofthe nasal cavity are continually oxidized by breathing, while the oralcavity is usually closed, except for speech or exhalation. Theexpression of carbon dioxide during speech or exhalation forms the basicbicarbonate ion (HCO₃)¹³ in saliva. These natural processes maintain thetwo compartments in different states of oxidation, with the nose at alower pH than the mouth. This gradient is maintained homeostatically,and results in a concentration cell.

This concentration cell can readily be observed using an oscilloscope orsensitive volt meter. Currents between these two compartments aregenerally approximately 80-100 milli-volts. These can be detected bytouching a probe or a wick electrode to the mucosa of both compartments.These values can also be calculated from the pH ranges in theliterature.

In order to deliver a bioactive material to an implanted device, thedirection of the electrical vector can be reversed to oppose the others,and maintain a charged medication or complex in the location of theimplanted device. Because the electrical vector has been reversed tooppose ordinary diffusion, delivery to an implanted device by thismethod keeps the bioactive material from leaving the site of theimplanted device for the time the electrical vector is present.Afterward, the forces of diffusion reassert themselves, and medicationdiffuses normally from the implantable device.

A stent can be used as a nonlimiting example of an implanted devicewhich can be charged or recharged by the method of the presentinvention. As shown in FIG. 2, the stent is in the form of a uniformcylindrical pipe 2 of length x and radius r. There is initially aconstant flow of blood through the stent. Although blood and lymph arenon-Newtonian fluids with changing viscosities, because of the alignmentand change of shape of cells during flow, these cells actually behave ina Newtonian manner during flow, i.e., they have a constant viscosity.

The stent 20 shown in FIG. 2 illustrates an implanted device. In thiscase:

A=hydrated cross sectional area of a charged drug particle

r=radius of the stent, a constant

x=length of the stent, a constant

N=viscosity of the fluid contained in the stent

V=dx/dt=velocity of the fluid through the stent, a variable

P=pressure, a variable

W=work, a constant

Sears and Zemansky, University Physics 10^(th) Edition, Young andFreedman, editors, on page 447 has the formula for a velocity through astent as illustrated above as:

V={(P ₂ −P ₁)(r₂₂ −r ₁₂)}/4Nx

The integration of Newton's law of force and viscosity given in U.S.Pat. No. 6,414,033, gives:

r=Wt/NA

Differentiating r with respect to t gives:

Dr/dt=W/NA

Application of the chain rule gives the expression for dr/dx:

Dr/dx=[4WX]/A(P ₂ −P ₁)(r22−r12)

The viscosity has been cancelled from the equation because the work termaccounts for viscosity.

The electrostatic work on the particle is:

W=zFE where E is the EMF calculated by any conventional means, such asthe Nernst or Boltzman equations.

Z=the valence of the ion, and F is the Faraday constant.

Thus the ion experiences continual force in the r direction and eithercontinual or intermittent motion in the x direction, depending upon whatassumption is made about the circulation. Accounting for the heartbeatof a relaxed patient, the blood remains stationary for from about 0.3 toabout 0.5 seconds per beat. At 60 beats per minute, this isapproximately 18 to 30 seconds added to the contact time in the stent,on a cumulative basis per minute. This can be added to the calculationsof travel from any given position for an ion in the lumen of the stent.

Given the induced charge on the stent, it is now possible to calculatethe time and force necessary to recharge it with an ionic medicationusing Stokes law:

F=force exerted on a spherical particle, and rp is the particle radius

F=6πNr_(p)dr/dt for the r direction, and dx/dt for the x direction. Inthe r direction this force is also equal to the EMF applied, and limitsthe speed of travel according to the viscosity.

In general, for an implanted device, the length of the implanted deviceis about 1 to about 10 cm in length. The speed of the circulation isintermittent, allowing more time for exchange. The force of dissociationof a charged particle or ligand complex must be less than that of theEMF applied, so that the molecule of bioactive material leaves thecomplex for the implanted device. The complex must discharge itsbiomedical material along the time given by the above equations, thatis, the time necessary for the particle to pass through the implanteddevice.

The system can be manipulated in a variety of ways:

1. controlling the induced charge on the implanted device

2. controlling the attractive force of the bioactive material moleculefor its complex versus the EMF applied by the implanted device.

3. the length of the implanted device

4. controlling the local viscosity of the blood or lymph

5. artificially slowing the heartbeat to achieve a longer contactbetween the fluids containing the bioactive material and the implanteddevice.

As long as the implantable device can be charged according to thepresent invention, it can be made of any physiologically compatiblematerial that can be used to hold another to release a bioactivematerial. Examples of such materials include stainless steel, tantalum,titanium , nitinol, gold, platinum, inconel, iridium, silver, tungsten,or alloys of these with each other or any other biocompatible metal;carbon, carbon fibers, cellulose acetate, cellulose nitrate, silicone,polyethylene terephthalate, polyurethane polyamide, polyester,polyorthoesters, polyanhydrides, polyether sulfones, polycarbonates,polypropylene, high molecular weight polyethylene,polytetrafluoroethylene, or other biocompatible polymer or mixtures ofcopolymers thereof; biodegradable materials such as polylactic acid,polyglycolic acid or mixture of copolymers thereof; proteins,extracellular matrix components; collagen, fibrin or other biologicagent; or a suitable mixture of any of these.

To move a positively charged (i.e., acid) bioactive material to theimplanted device, the implanted device must be negatively charged withrespect to the bioactive material. Conversely, to move a negativelycharged (i.e., basic) bioactive material to the implanted device, theimplanted device must be positively charged with respect to thebioactive material.

Alternatively, the bioactive material may be in the form of a neutralcomplex of the bioactive material and a suitable carrier molecule, suchthat the Kd of the carrier is less than the electrostatic force ofattraction exerted by the implanted device for the bioactive agent.Amino acids and their congeners are ideal carriers, although, given therequirement that the Kd of the carrier be less than the electrostaticforce of attraction exerted by the implanted device for the bioactivematerial, one skilled in the art can readily design an appropriatecarrier for the bioactive material.

Examples of bioactive agents that can be delivered to an implanteddevice by the method of the present invention include antiplatelets,anticoagulants, antifibrins, antithrombins, and antiproliferatives.Other bioactive agents which can be used in the present inventioninclude cytostatic agents, angiotensin converting agents, calciumchannel blockers, prostaglandin inhibitors, monoclonal antibodies,phosphodiesterase inhibitors, serotonin blockers, steroids, thioproteaseinhibitors, PDGF antagonists, and nitric oxide. Other bioactivematerials include alpha-interferon and genetically engineered epithelialcells.

For example, to charge a stent implanted in a blood vessel, anantiproliferative agent such as methotrexate is delivered to the stentto inhibit over-proliferation of smooth muscle cells and thus inhibitrestenosis of the dilated segment of the blood vessel. Additionally,localized delivery of an antiproliferative agent is also useful fortreating a variety of malignant conditions characterized by rapidvascular growth. In such cases, the implantable device can be placed inthe arterial supply of the tumor to provide a means for delivering arelatively high dose of the antiproliferative agent directly to thetumor.

A variety of other bioactive materials are suitable for use when theimplantable device is configured as something other than a coronarystent. For example, an anti-cancer chemotherapeutic agent can bedelivered by the device to a localized tumor. More particularly, theimplantable device can be placed into an artery supplying blood to thetumor or elsewhere to deliver a relatively high and prolonged dose ofthe agent directly to the tumor, while limiting systemic exposure andtoxicity. The agent may be a curative, a pre-operative debulker forreducing the size of the tumor, or a palliative which eases the symptomsof the disease. It should be noted that the bioactive material in thepresent invention is delivered directly from the implanted device, andnot by passage from an outside source through any lumen defined in thedevice. The bioactive material of the present invention may, of course,be released from the device into any lumen defined in it, and that lumenmay carry some other agent to be delivered through it.

Dopamine, or a dopamine agonists such as bromocriptine mesylate orpergolide mesylate is useful in treating neurological disorders such asParkinson's disease. The device could be placed into the vascular supplyof the thalamic substantia nigra for this purpose, or elsewhere,localizing treatment in the thalamus.

A wide range of other bioactive materials can be delivered to theimplanted device for treatment of a variety of conditions. Nonlimitingexamples of such bioactive materials include paclitaxel, estrogen orestrogen derivatives, heparin or another thrombin inhibitor;antithrombogenic agent such as hirudin, hiruolog, argatoban,D-phenylalanyl-L-poly-L-arginiyl chloromethyl ketone, or mixturesthereof; urokinase, streptokinase, tissue plasminogen activator, orother thrombolytic agent or mixtures thereof; a fibrinolytic agent; avasospasm inhibitor; a calcium channel blocker; a nitrate, nitric oxide,a nitric oxide promoter or other vasodilator; an antimicrobial agent orantibiotic; aspirin, ticlopidine or other antiplatelet agent;antimitotics such as colchicines or another microtubule inhibitor;cytochalasin or other actin inhibitor; a remodeling inhibitor;cytochalasin or other actin inhibitor; deoxyribonucleic acid, anantisense nucleotide or another agent for molecular geneticintervention; GP IIa/IIIa, GP Ib-IX or another inhibitor of surfaceglycoprotein receptor; methotrexate or another antimetabolite orantiproliferative agent; anti-cancer chemotherapeutic agents;anti-inflammatory steroids; immunosuppressive agents; antibiotics;dopamine or bromocriptine mesylate, pergolide mesylate or other dopamineagonist; ^(6O)Co, ¹⁹²Ir, ³²p, ¹¹¹In, ⁹⁰y, ⁹⁹Tc, or anotherradiotherapeutic agent; iodine-containing compounds, barium-containingcompounds, gold, tantalum, platinum, tungsten or another heavy metalfunctioning as a radiopaque agent; a peptide, a protein, an enzyme, anextracellular matrix composition, a cellular component or anotherbiological agent; captopril or other angiotensin converting enzymeinhibitor; ascorbic acid, alphatocopherol, superoxide dismutase, orother free radical scavenger, iron chelator or antioxide; angiopeptin;radiolabelled elements or compounds; or mixtures of any of these.

Disease states in which one would deliver bioactive materials involving“angiogenic activity” include, but are not limited to, myocardialconditions, trauma, tumors (benign and malignant) and tumor metastases,ischemia, tissue and graft transplantation, diabetic microangiopathy,neovascularization of adipose tissue and fat metabolism,revascularization of necrotic tissue, eye conditions (e.g., retinalneovascularization), growth of new hair, and ovarian folliclematuration.

While the foregoing types of bioactive materials have been used to treator prevent restenosis and other conditions, they are provided by way ofexample and are not meant to be limiting, since other bioactive agentscan be introduced in the same manner. Treatment of diseases using theabove bioactive materials are known in the art. Furthermore, thecalculation of dosages, dosage rates, and appropriate duration oftreatment are well known in the art.

The implanted medical device can be designed for continuousadministration of a bioactive material. In this case, the bioactivematerial can be periodically administered to the patient either byintravenous or transmembrane techniques. The amount of bioactivematerial to be administered each time depends on the rate of absorptionof the material from the stent into the blood, which can be eitherhigher or lower than the conventional therapeutic dosage, since thebioactive material is administered directly to the site of releaserather than through the digestive system, etc.

The present invention provides a non-invasive method for charging animplanted device with a bioactive material, or for re-charging animplanted device with a bioactive material.

The foregoing description of the specific embodiments will so fullyreveal the general nature of the invention that others can, by applyingcurrent knowledge, readily modify and/or adapt for various applicationssuch specific embodiments without departing from the generic concept,and, therefore, such adaptions and modifications should and are intendedto be comprehended within the meaning and range of equivalents of thedisclosed embodiments. It is to be understood that the phraseology orterminology employed herein is for the purpose of description and not oflimitation.

What is claimed is:
 1. A method for charging or re-charging an implanteddevice with a bioactive material comprising: a. introducing a chargeinto the implanted device; b. introducing a bioactive material in ionicform or in a neutral complex that will dissociate tonically in thepresence of the charge on the implanted device.
 2. The method accordingto claim 1 wherein the implanted device is a stent.
 3. The methodaccording to claim 2 wherein the bioactive material is a material fortreating or preventing restenosis.
 4. The method according to claim 1wherein the bioactive material is introduced intravenously ortrans-membrane.
 5. The method according to claim 1 wherein the bioactivematerial is in the form of a neutral complex of the bioactive materialand a carrier molecule for the bioactive ingredient.
 6. The methodaccording to claim 5 wherein the carrier is an amino acid or a congenerthereof.
 7. The method according to claim 5 wherein the carrier is amolecule such that the KD of the carrier is less than the electrostaticforce of attraction exerted by the bioactive material.
 8. The methodaccording to claim 1 wherein the bioactive material is in the form of astable charged complex with a direct attraction for the charge in theimplanted device.
 9. The method according to claim 1 wherein thebioactive material is selected from the group consisting of ananti-proliferative agent, an anti-cancer therapeutic, dopamine, adopamine agonist, a thrombin inhibitor, an estrogen, an androgen, anantithrombogenic agent, a clot dissolver, a fibrinolytic agent, avasospasm inhibitor, a calcium channel blocker, a vasodilator, anantimicrobial agent, an antibiotic, an antiplatelet agent, anantimitotic, an actin inhibitor, a remodeling inhibitor, a deoxynucleicacid, an antisense nucleotide, an inhibitor of surface glycoproteinreceptor, a steroid, an immunosuppressive agent, a radiotherapeuticcompound, a radiopaque agent, a peptide, a protein, an enzyme, anextracellular matrix composition, an angiotensin converting enzymeinhibitor, a free radical scavenger, and mixtures thereof.
 10. Animplantable device which is capable of being charged or re-chargedwithout removal from the body in which it is implanted comprising adevice made of material which can be induced to form a charge and toretain the charge sufficiently long to act electrostatically and attracta charged substance to itself.
 11. The device according to claim 10which is in the form of a stent.
 12. The device according to claim 11wherein the bioactive material is a material for treating or preventingrestenosis.
 13. The device according to claim 10 which is made of abiocompatible material selected from the group consisting of plastichaving metal atoms covalently bonded thereto, ceramic having metal atomscovalently bonded thereto, ceramic having an electronic transfer system,and porous metals in which a bioactive material is embedded therein. 14.The device according to claim 10 wherein a metallic or capacitive stripis embedded within the device.